1. Field of the Invention
The present invention relates to pharmaceutically active compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are particularly useful for the treatment or prophylaxis of diseases associated with parasitic infection, such as toxoplasmosis, cryptosporidiosis, leischmaniasis and malaria.
2. Background
Parasitic-related diseases are highly prevalent and often difficult to treat. For example, toxoplasmosis, caused by the parasitic protozoan Toxoplasma gondii, is a leading cause of morbidity and morality in patients with AIDS as well as in other immunocompromised patients such as persons receiving immunosuppressive cancer chemotherapy. Toxoplasmosis also is suffered by the developing fetus with the potential result of severe neurological damage. The disease is also problematic for livestock and other domesticated animals. For example, toxoplasmosis causes spontaneous abortion in sheep.
Pneumocytis pneumonia, cryptosporidiosis, leischmaniasis and malaria also result from parasitic infection and can be difficult to treat, particularly in immunocompromised subjects. Pneumocytis pneumonia results from infection by Pneumocystis carinii, a fungal parasite which is benign in immunocomponent individuals but can be life-threatening in patients with AIDS. Cryptosporidiosis results from infection of protozoa of the genus Cryptosporidium and, in the case of immunocompromised individuals, the disease can be chronic and life threatening. Leischmaniasis is any of a group of conditions resulting from Leishmania infection. Manifestations of leischmaniasis are significantly enhanced in the immunocompromised. Malaria can result from infection of several different parasites: Plasmodium vivax, P. falciparum, P. malarie, and P. ovale. See generally The Merck Manual, 16th edition.
Current therapies to treat toxoplasmosis and other parasitic infections have included use of trimethoprim and pyrimethamine. See Merck Index 8169 and 9840 (12th edition.). However, these agents are often not sufficiently potent to be fully effective when used alone and, consequently, the agents are typically administered in combination with a sulfa drug.
That combination drug therapy, however, has clear shortcomings. Many patients exhibit severe allergic reactions to sulfa drugs, and the therapy must be discontinued prior to effective treatment of the disease.
It thus would be desirable to have new therapies to treat parasitic related diseases, such as toxoplasmosis, cryptosporidiosis, leischmaniasis and malaria.